title: A potent anti-CD70 antibody-drug conjugate combining a dimeric pyrrolobenzodiazepine drug with site-specific conjugation technology.
abstract: A highly cytotoxic DNA cross-linking pyrrolobenzodiazepine (PBD) dimer with a valine-alanine dipeptide linker was conjugated to the anti-CD70 h1F6 mAb either through endogenous interchain cysteines or, site-specifically, through engineered cysteines at position 239 of the heavy chains. The h1F6239C-PBD conjugation strategy proved to be superior to interchain cysteine conjugation, affording an antibody-drug conjugate (ADC) with high uniformity in drug-loading and low levels of aggregation. In vitro cytotoxicity experiments demonstrated that the h1F6239C-PBD was potent and immunologically specific on CD70-positive renal cell carcinoma (RCC) and non-Hodgkin lymphoma (NHL) cell lines. The conjugate was resistant to drug loss in plasma and in circulation, and had a pharmacokinetic profile closely matching that of the parental h1F6239C antibody capped with N-ethylmaleimide (NEM). Evaluation in CD70-positive RCC and NHL mouse xenograft models showed pronounced antitumor activities at single or weekly doses as low as 0.1 mg/kg of ADC. The ADC was tolerated at 2.5 mg/kg. These results demonstrate that PBDs can be effectively used for antibody-targeted therapy.
authors.affiliation: Department of Research & Translational Medicine, Seattle Genetics, Inc., Bothell, WA 98021, USA. sjeffrey@seagen.com
authors.forename: Scott C
authors.initials: SC
authors.lastname: Jeffrey
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Burke
authors.forename: Robert P
authors.initials: RP
authors.lastname: Lyon
authors.forename: David W
authors.initials: DW
authors.lastname: Meyer
authors.forename: Django
authors.initials: D
authors.lastname: Sussman
authors.forename: Martha
authors.initials: M
authors.lastname: Anderson
authors.forename: Joshua H
authors.initials: JH
authors.lastname: Hunter
authors.forename: Chris I
authors.initials: CI
authors.lastname: Leiske
authors.forename: Jamie B
authors.initials: JB
authors.lastname: Miyamoto
authors.forename: Nicole D
authors.initials: ND
authors.lastname: Nicholas
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Okeley
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Sanderson
authors.forename: Ivan J
authors.initials: IJ
authors.lastname: Stone
authors.forename: Weiping
authors.initials: W
authors.lastname: Zeng
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Gregson
authors.forename: Luke
authors.initials: L
authors.lastname: Masterson
authors.forename: Arnaud C
authors.initials: AC
authors.lastname: Tiberghien
authors.forename: Philip W
authors.initials: PW
authors.lastname: Howard
authors.forename: David E
authors.initials: DE
authors.lastname: Thurston
authors.forename: Che-Leung
authors.initials: CL
authors.lastname: Law
authors.forename: Peter D
authors.initials: PD
authors.lastname: Senter
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000737:chemistry*; D053282:CD27 Ligand / Q000737:chemistry*; D019281:Dimerization; D015195:Drug Design; D005260:Female; D006207:Half-Life; D018796:Immunoconjugates / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D053282:CD27 Ligand; C505771:CD70 protein, human; D018796:Immunoconjugates; D001569:Benzodiazepines